This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. SIV infection in rhesus macaques of Chinese origin (Ch Rh) results in one-third of long-term nonprogressing macaques. We used this model for continuous study of the role of natural killer (NK) cells in the establishment of long-term nonprogressing state in LTNP Ch Rh, which could be translated into vaccine development for HIV-1 infection. We found that NK cells have 2 major subsets: CD3-CD8+CD16+ and CD3-CD8+CD16-, similar to that in humans. The distribution and function of these 2 subsets in peripheral blood and in the intestinal mucosa are different. The CD16+ subsets decreased progressively following SIV infection. Furthermore, we found, for the first time, that programmed death 1 (PD-1) expressed on NK cells in acute infection. Remarkably, PD-1 expression may be beneficial to NK cell antiviral functions, which is in contrast to its negative regulation of T cells (T cell dysfunction or exhaustion) during chronic SIV/HIV infection. We also found that NKp46 expressed NK cells had a positive correlation with the secretion of cytokine IL-22 in the gut, indicating that this subset of NK cells may provide important innate mucosal immune defense in SIV or HIV-1 infection. Overall, NK cells are likely much more important than previously thought, particularly they posses new memory-like "adaptive" features that has been discovered recently. Thus, reevaluation of the role of NK cells in HIV/SIV infection is essential.